American Journal of Obstetrics and Gynecology (2006) 194, 1206

www.ajog.org

GENERAL OBSTETRICS AND GYNECOLOGY: OBSTETRICS

Spirometry is related to perinatal outcomes in pregnant women with asthma

Michael Schatz, MD, MS,a,* Mitchell P. Dombrowski, MD,b Robert Wise, MD,c Valerija Momirova, MS,d Mark Landon, MD,e William Mabie, MD,f Roger B. Newman, MD,g Dwight J. Rouse, MD, MSPH,h Marshall Lindheimer, MD,i Menachem Miodovnik, MD,j Steve N. Caritis, MD,k Kenneth J. Leveno, MD,l Paul Meis, MD,m Ronald J. Wapner, MD,n Richard H. Paul, MD,o Mary Jo OSullivan, MD,p Michael W. Varner, MD,q Gary R. Thurnau, MD,r Deborah L. Conway, MD,s for The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, and The National Heart, Lung, and Blood Institute, Bethesda, MD
Department of Allergy, Kaiser Permanente, San Diego, CA a; Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI b; Department of Pulmonary Medicine, Johns Hopkins University, Baltimore, MDc; Biostatistics Center, George Washington University, Washington, DCd; Department of Obstetrics and Gynecology, Ohio State University, Columbus OH e; Department of Obstetrics and Gynecology, University of Tennessee, Memphis, TN f; Department of Obstetrics and Gynecology, Medical College of South Carolina, Charleston, SCg; Department of Obstetrics and Gynecology, University of Alabama, Birmingham, ALh; Department of Obstetrics and Gynecology, University of Chicago, Chicago, ILi; Department of Obstetrics and Gynecology, University of Cincinnati, Cincinnati, OH j; Department of Obstetrics and Gynecology, University of Pittsburgh-Magee Womens Hospital, Pittsburgh, PAk; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TXl; Department of Obstetrics and Gynecology, Wake Forest University, Winston-Salem, NCm; Department of Obstetrics and Gynecology, Drexel University, Philadelphia, PAn; Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CAo; Department of Obstetrics and Gynecology, University of Miami, Miami, FLp; Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT q; Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, OKr; Department of Obstetrics and Gynecology, University of Texas, San Antonio, TX s
Received for publication March 15, 2005; revised April 19, 2005; accepted June 3, 2005

Supported by grants from the National Institute of Child Health and Human Development (HD21410, HD21414, HD21434, HD27869, HD27917, HD27905, HD27889, HD27860, HD27861, HD27915, HD27883, HD34122, HD34116, HD34208, HD34136, HD19897, HD36801, HD34210) and the National Heart Lung and Blood Institute. * Reprint requests: Michael Schatz, MD, MS, Chief, Department of Allergy, Kaiser-Permanente Medical Center, 7060 Clairemont Mesa Blvd, San Diego, CA 92111. E-mail: michael.x.schatz@kp.org

0002-9378/$ - see front matter 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.06.028

Schatz et al KEY WORDS

Asthma Pregnancy Forced expiratory volume in 1 second Symptom Prematurity Preeclampsia

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Objective: The purpose of this study was to test the hypothesis that maternal asthma symptoms and pulmonary function are related to adverse perinatal outcomes. Study design: Asthmatic patients were recruited from the 16 centers of the Maternal Fetal Medicine Units. Forced expiratory volume in 1 second was obtained at enrollment and at monthly study visits, and the frequency of asthma symptoms was assessed from enrollment to delivery. Perinatal data were obtained at postpartum chart reviews. Results: The final cohort included 2123 participants with asthma. After adjustment for demographic characteristics, smoking, acute asthmatic episodes, and oral corticosteroid use, significant relationships were demonstrated between gestational hypertension and preterm birth and lower maternal gestational forced expiratory volume in 1 second. The data did not show any significant independent relationship between asthma symptom frequency and perinatal outcomes. Conclusion: Lower pulmonary function during pregnancy is associated with increased gestational hypertension and prematurity in the pregnancies of women with asthma, which may be due to inadequate asthma control or factors that are associated with increased asthma severity. 2006 Mosby, Inc. All rights reserved.

Asthma may be the most common potentially serious medical problem to complicate pregnancy.1 Several studies have reported increased incidences of preeclampsia, preterm birth, or lower birth weight in infants of mothers with asthma, especially more severe asthma, compared with nonasthmatic control subjects.2-5 Two main potentially remedial mechanisms have been postulated to explain these observations6: (1) poor asthma control that leads to fetal hypoxia and (2) asthma medications, specically corticosteroid treatment. In addition, common pathogenetic factors could explain the association between maternal asthma and adverse perinatal outcomes,6 although this relationship would presumably be less responsive to intervention. The Maternal Fetal Medicine Units (MFMU) asthma observational cohort study was designed to evaluate the relationships between asthma severity, control, and treatment during pregnancy and the maternal and fetal morbidity in a large cohort of pregnant asthmatic patients and matched control subjects. Although this study demonstrated a strong relationship between gestational asthma severity and asthma morbidity during pregnancy,7 it did not nd a relationship between asthma exacerbations during pregnancy and adverse perinatal outcomes.8 Independent relationships were demonstrated in this study between the use of oral corticosteroids and increased incidences of preterm birth at !37 weeks of gestation and a birth weight of !2500 g, but not gestational hypertension or small for gestational age babies.9 Forced expiratory volume of air expired in one second (FEV1) is a standardized measure of airway obstruction and is used to reect both asthma severity10 and degree of asthma control.11 One previous study has reported a direct relationship between mean maternal FEV1 during pregnancy and infant birth weight.12 Because FEV1 and symptom frequency were evaluated at each visit, the MFMU study provided an opportunity to test the hypothesis that increased asthma burden, as

measured by either more symptoms or lower FEV1, is related to adverse perinatal outcomes, after adjustment for medication use and other important covariates.

Material and methods

Patients in this report were asthmatic participants in either the MFMU asthma observational cohort study7,8 or the MFMU randomized controlled trial of beclomethasone versus theophylline for moderate asthma during pregnancy.13 These studies were conducted at 16 centers of the MFMU Network of National Institute of Child Health and Human Development, with recruitment from December 1994 to February 2000. Asthma was dened in these studies as a history of physician-diagnosed asthma, which has been shown to be a valid denition of asthma for epidemiologic studies.14 Severity classication was based on the 1993 Working Group Report.15 In the observational cohort study, asthmatic patients with all levels of severity were enrolled and monitored, but treatment was determined by the patients individual physician. The observational cohort study included 873 participants with mild asthma, 814 participants with moderate asthma, and 52 participants with severe asthma. By recruitment design, the proportion of participants who smoked was balanced between the mild and moderate/severe cohorts. In the randomized controlled trial, only patients with moderate asthma were enrolled; patients were assigned randomly to treatment with inhaled beclomethasone (n = 194) or theophylline (n = 190), and treatment was by study protocol. During the time period that the 2 studies were running concurrently (December 1995-March 1999), patients with moderate asthma were rst oered entry into the randomized controlled trial, and, if they declined, they were then oered entry into the observational cohort study. The following methods were used in both studies. Case nding was by questioning all obstetric patients

122 about having physician-diagnosed asthma. Informed written consent was obtained from all participants, and the study was approved by each institutions local Institutional Review Board. Participants were excluded for known multiple gestation, gestational hypertension, intrauterine fetal death, major congenital abnormalities, active pulmonary disease other than asthma, inability to schedule an ultrasound examination for gestational age conrmation, or gestational age O25 weeks and 6 days at intake. Spirometry (O4 hours after bronchodilator use) was performed on all participants at enrollment. Measurements of FEV1 were made with the subject standing, after a maximal inspiration. To standardize spirometry techniques, all centers used Collins Stead-Well dry-seal volume displacement spirometers (W. E. Collins, Baintree, MA), and all research nurses underwent a training and quality review program. FEV1 was expressed as the percent of predicted FEV1, based on age, gender, height, and ethnicity, with a 0.88 adjustment for black race.16 An FEV1 measurement and information regarding symptom frequency since the previous visit (number of days with any asthma symptoms, number of nights that asthma interfered with sleep, and number of days that asthma interfered with activity) were obtained on each monthly visit. In addition, asthma medication use and the occurrence of asthma hospitalizations or unscheduled visits (physician oce or emergency department) were assessed at these monthly visits. The gestational age at the time of study entry was determined from the last menstrual period if it correlated with the rst ultrasound examination. Dating was based on the rst ultrasound examination if the last menstrual period estimate varied by O7 days from the ultrasound gestational age estimate if the rst ultrasound examination was performed at !20 weeks of gestation or by O14 days if the initial ultrasound examination was performed between 20 and 26 weeks of gestation. Perinatal data was obtained at postpartum chart reviews. Perinatal outcome variables included (1) gestational hypertension, (2) preterm birth at !37 weeks of gestation, (3) preterm birth at !32 weeks of gestation, (4) low birth weight (!2500 g), (5) small for gestational age (!10th percentile), and (6) major malformations at birth (including multiple malformation syndromes), as classied by an independent dysmorphology specialist based on descriptions by the attending pediatricians/ neonatologists. Gestational hypertension was dened as 2 blood pressure measurements of R140/90 mm Hg (R4 hours apart) at or beyond gestational age of 20 weeks and/or a clinical diagnosis of preeclampsia, eclampsia, or hemolysis, elevated liver function, and low platelet count (HELLP) syndrome. The continuous predictors of interest were mean FEV1 (ie, the mean percent predicted FEV1 across all of the

Schatz et al measurements for an individual during the study, including the measurement at enrollment) and mean percentage of days from enrollment to delivery with any asthma symptoms, interference with sleep, and interference with activity. To identify a threshold eect of airway obstruction or symptoms, we dened uncontrolled asthma during the course of pregnancy as not achieving mild intermittent status according to the National Asthma Education and Prevention Program guidelines.10 This was operationalized as the following outcomes: (1) proportion of patients whose mean FEV1 that was calculated across all measurements during the study was !80% of the patients predicted FEV1, (2) asthma symptoms on R25% of days, (3) interference with sleep on R10% of nights, and (4) interference with activity on R10% of days. Potentially relevant covariates included maternal parity, age, smoking, black ethnicity, prepregnancy weight, use of oral corticosteroids, and unscheduled asthma visits (hospital, emergency department, or oce) during pregnancy. Analyses of preterm births were also adjusted for previous preterm births as a covariate because this has been shown to be a risk factor for subsequent preterm births.17 A relationship between individual patient mean FEV1 or mean symptoms and the birth weight of her infant was evaluated by means of Spearman correlation coefcient. Univariate data for perinatal outcomes were analyzed by means of Wilcoxon tests for continuous predictors and by chi-square analysis for dichotomous predictors. For outcomes that were found to be related signicantly to FEV1 or symptoms in univariate analyses, multivariable analyses were performed with logistic regression techniques. Two-tailed statistical tests were used for univariate analyses. Nominal statistical significance was set at a probability value of !.05.

Results
The nal cohort included 2123 asthmatic participants (Table I) whose ages ranged from 13 to 44 years (mean, 23 years). Less than one half of the patients were nulliparous, and more than one half of the patients were black. Nearly one third of the patients required unscheduled asthma visits. Approximately 18% of the patients smoked. The mean percent predicted FEV1 during pregnancy ranged from 22% to 155% (mean, 94%), and 17% of the patients had a mean FEV1 across pregnancy of !80% of their predicted value. The symptoms results in the observational cohort, randomized controlled trial, and total samples are also shown in Table I. A small (r = .08) but signicant (P = .0001) correlation was found between individual patient mean FEV1 and the birth weight of her infant. No signicant correlations were found between infant mean birth weight and maternal percentage of days of any asthma symptoms (r = .008), percentage of nights with sleep

Schatz et al
Table I Parameter N Age range (y)* Nulliparous (%) Smokers (%) African American race (%) Patients with unscheduled asthma visits: Hospital, emergency department, ofce (%) Predicted FEV1 range (%)* Patients with mean FEV1 across pregnancy !80% predicted (%) Days with any asthma symptoms (%)* Nights with sleep interference (%)* Days with activity limitation (%)* Patients with any symptoms R25% (%) Patients with interference with sleep R10% of nights (%) Patients with interference with activity R10% of days (%) Use of oral steroids (%) Gestational hypertension (%) Preterm birth: !37 wk (%) Preterm birth: !32 wk (%) Low birth weight: !2500 g (%) Small for gestational age: !10% (%) Major malformations (%)
* Data are given as range (mean G SD).

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Characteristics of the participants with asthma Observational cohort 1739 13-44 (23 G 6) 45.1 18.7 55.5 31.9 22-138 (94 G 14) 15.7 0-100 (22.3 G 23.6) 0-100 (12.5 G 18.6) 0-100 (7.2 G 13.9) 32.0 34.7 21.9 8.1 12.3 16.0 3.2 13.7 7.1 1.9 Randomized controlled trial 384 14-42 (23 G 6) 38.5 16.9 62.5 38.8 54-155 (92 G 14) 21.1 0-100 (32.8 G 27.3) 0-100 (15.0 G 21.1) 0-99 (8.4 G 14.9) 50.5 41.9 23.4 11.5 8.1 17.7 3.9 13.9 7.0 2.3 Total participants 2123 13-44 (23 G 6) 43.9 18.4 56.8 33.2 22-155 (94 G 14) 16.7 0-100 (24.2 G 24.7) 0-100 (13.0 G 19.1) 0-100 (7.4 G 14.1) 35.4 36.0 22.2 8.7 11.5 16.3 3.3 13.7 7.1 2.0

interference (r = .006), or percentage of days with activity limitation (r = .005). Mean FEV1 was significantly lower in pregnancies with gestational hypertension, preterm births at !37 weeks of gestation, and low birth weight infants compared with patients who did not experience those adverse perinatal outcomes (Table II). Signicantly more patients with preterm births (!32 and !37 weeks of gestation) and low birth weight infants manifested mean FEV1 across pregnancy !80% of predicted compared with patients without those outcomes (Table III). No signicant relationships were demonstrated between either FEV1 variable and small for gestational age infants. Although the proportion of mothers of infants with major malformations who demonstrated a mean FEV1 across pregnancy of !80% of predicted was lower than that proportion in mothers of infants without major malformations, that dierence was not signicant (P = .09; Table III). In addition, there was only a minimal dierence in mean FEV1 between mothers of infants with or without major malformations (Table II). There were no signicant relationships demonstrated between mean symptom parameters and any perinatal outcome (data not shown). More patients with interference with activity on R10% of days experienced preterm birth at !37 weeks of gestation compared with

those patients with interference with activity on !10% of days (20.0% vs 15.3%; P = .015), but no other relationships between uncontrolled asthma based on cut-o symptom parameters and perinatal outcomes were observed (data not shown). The independent relationships between FEV1 variables and perinatal outcomes are shown in Table IV. After an adjustment for covariates, signicant relationships were demonstrated between gestational hypertension and preterm births (!37 and !32 weeks of gestation) and mean FEV1 and/or proportion with mean FEV1 across pregnancy !80% of predicted. After an adjustment for covariates, neither mean percentage of days of activity limitation nor activity limitation R10% of days were associated signicantly with preterm births at !37 weeks of gestation (data not shown).

Comment
Asthma has been reported recently to complicate up to 8% of pregnancies,1 which makes it the most common potentially serious medical problem to occur during pregnancy. Data regarding the eect of maternal asthma on pregnancy have been conicting,6 but the largest and most recent study suggested that pregnancies in women

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Table II Outcome Gestational hypertension Preterm !32 wk Preterm !37 wk Low birth weight Small for gestational age Major malformations
* Data in parentheses represents the number of patients. y P ! .05 (Wilcoxon). z P ! .01 (Wilcoxon).

Schatz et al
The relationships between mean FEV1 and perinatal outcomes in all subjects Mean G SD% predicted FEV1* Outcome present 91.4 89.5 91.4 91.5 92.5 92.8 G G G G G G 14.3 (244) 16.7 (71) 15.6z (346) 14.7y (289) 14.8 (150) 9.5 (42)
y

Outcome absent 93.7 93.5 93.8 93.7 93.5 93.4 G G G G G G 14.2 14.1 13.9 14.1 14.2 14.3 (1874) (2052) (1777) (1818) (1964) (2081)

Table III The relationships between mean FEV1 across pregnancy that are !80% predicted and perinatal outcomes Incidence of outcome (%) Mean FEV1 across pregnancy !80% predicted (n = 354) Mean FEV1 across pregnancy R80% predicted (n = 1769) 11.2 3.0 15.3 12.9 7.0 2.2

Table IV Adjusted odds ratios for the relationship between FEV1 variables and perinatal outcomes* Adjusted odds ratio (95% CI) Mean FEV1 percent predictedy 0.98 0.99 0.98 0.99 (0.97-0.99)x (0.98-1.00) (0.96-1.00)x (0.98-1.00) Mean FEV1 across pregnancy !80% predictedz 1.30 1.36 1.85 1.38 (0.91-1.87) (1.01-1.84)x (1.05-3.28)x (1.00-1.90)x

Perinatal outcome Gestational hypertension Preterm !37 wkk Preterm !32 wkk Low birth weight !2500 g

Outcome

Gestational hypertension 13.0 Preterm !32 wk 5.1* Preterm !37 wk 21.2y Low birth weight 17.6* Small for gestational age 7.4 Major malformations 0.8
* P ! .05 (chi-square test). y P ! .01 (chi-square test).

* Adjusted for maternal parity, age, smoking, black race, prepregnancy weight, unscheduled (hospital, emergency department, ofce) visits, and oral steroids. y Odds ratio per 1 unit change in the percent predicted; multiple linear regression. z Multiple logistic regression. k Also adjusted for previous preterm birth. x P ! .05.

with asthma are more likely to be complicated by preeclampsia, preterm birth, or lower birth weight compared with pregnancies of nonasthmatic women.4 Three potential mechanisms have been proposed to account for this increased risk6: (1) poor asthma control that leads to maternal and fetal hypoxia, (2) asthma medications such as corticosteroids, and (3) common pathogenetic factors that cause both asthma and perinatal complications. Two previous studies have reported a relationship between poor asthma control, as dened by hospitalization during pregnancy, and lower infant birth weight.18,19 However, these studies did not adjust for other factors, which included antenatal corticosteroid use. One previous study12 reported a direct relationship between mean maternal FEV1 during pregnancy and infant birth weight in asthmatic women and an inverse relationship between mean FEV1 during pregnancy and intrauterine growth retardation (as assessed by low ponderal indices). The latter relationship was independent of acute asthmatic episodes, smoking, and medication use. A more recent study reported a relationship between daily asthma symptoms

and an increased risk of small for gestational age infants in a cohort of pregnant asthmatic patients.20 The current data support and extend the aforementioned FEV1 ndings, which suggests a direct relationship between maternal FEV1 during pregnancy and infant birth weight and an inverse relationship to gestational hypertension and preterm birth. Because FEV1 can be a measure of asthma control,11 these data could support the hypothesis that improved asthma control during pregnancy is associated with reduced adverse perinatal outcomes. The current data do not support the alternate hypothesis that medications are responsible for the increased risks, because no signicant relationship between the use of inhaled beta agonists, theophylline, or inhaled steroids and adverse perinatal outcomes were demonstrated in this study9 and because the current relationships between adverse perinatal outcomes and FEV1 were signicant, even after an adjustment for oral steroid use. Our study showed almost no relationships of asthma symptom measures to perinatal outcomes. Only activity

Schatz et al limitation R10% was related to preterm birth in univariate, but not multivariable, analyses. It is possible that the activity limitation in such patients could have been due to the pregnancy (eg, prescribed bed rest for preterm labor) rather than because of asthma. Alternatively, the multiple comparisons in this study may have provided one statistically signicant relationship by chance alone. Our negative ndings are in contrast to those of Bracken et al,20 who found a signicant relationship between symptom frequency and intrauterine growth retardation. However, their study reported a signicant eect only with daily symptoms and did not nd a signicantly increased risk with lesser frequencies of symptoms. Because only approximately 3% of our patients had symptoms on O90% of days, the current study would not have sucient power to demonstrate such an eect. Consistent with our results, symptom frequency in their cohort was not related to preterm birth.20 Studies have shown that asthma symptoms correlate poorly with spirometry,21 and the current data show that perinatal outcomes are related more closely to spirometry than to symptoms. This may be because chronic maternal hypoxia is better reected by reduced spirometry than by increased symptoms. Although FEV1 can be a measure of asthma control,11 it can also be a measure of asthma severity. Thus, the current data are also consistent with the hypothesis that common pathogenetic factors in patients with more severe asthma cause both the more severe asthma and the perinatal complications. Such factors could include autonomic nervous system dysfunction, intrinsic smooth muscle abnormalities, proinammatory mechanisms, and mediators (such as angiotensin or endothelin) that can cause both vasoconstriction and bronchial constriction.6 Further studies that are designed specically to assess these common pathogenetic factors along with parameters of asthma severity, control, and treatment will be necessary to clarify the mechanisms of the relationship between FEV1 and perinatal outcomes that were demonstrated in this and the previous studies.12 An alternative and simpler measure of pulmonary function is the peak expiratory ow rate, which can be used at home or in the oce to follow patients with asthma. However, we chose the FEV1 for this study because it is more reproducible, is less eort dependent and equipment dependent, has better dened predicted values,14 and is more specically related to asthma severity10 and control11 than the peak expiratory ow rate. In addition, changes in FEV1 in asthmatic patients during pregnancy can be ascribed to asthma because studies have reported no change in FEV1 because of pregnancy itself.15 Although the mechanisms of the associations in this study are not dened, the current study does suggest that the regular measurement of FEV1 during pregnancy is important, both as a measure of asthma control/

125 severity and as a prognostic factor for perinatal outcome. In particular, frequent values of !80% of predicted may be most meaningful in this regard. Although these ndings provide potential insight into the pathophysiology of adverse pregnancy outcomes that are related to low FEV1, further study is needed to delineate the impact of intervention that is based on these ndings and subsequent pregnancy outcome.

Acknowledgments
In addition to the authors, the following list comprises other members of the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network: University of Pittsburgh: R. Phillip Heine, M. Cotroneo, E. Daugherty; University of Tennessee: B. Sibai; University of Southern California: Y. Rabello; University of Alabama at Birmingham: W. W. Andrews, R. L. Copper, S. Tate, A. Northen; Wayne State University: Y. Sorokin, A. Millinder; University of Cincinnati: N. Elder, T. A. Siddiqi, V. Pemberton; Wake Forest University: M. Harper, M. Swain, A. Luper; University of Oklahoma: J. C. Carey, A. Meier; University of Chicago: P. Jones, M. E. Brown, G. Mallett; MUSC: J. P. Van Dorsen, B. A. Collins; Ohio State University: F. Johnson, S. Meadows; University of Miami: S. Beydoun, C. Alfonso, J. Potter; University of Texas Southwestern Medical Center: M. L. Sherman; University of Texas at San Antonio: S. Barker, O. Langer; Thomas Jeerson University: M. DiVito, K. Smith; The George Washington University Biostatistics Center: E. Thom, E. Rowland, S. Brancolini. We would like to thank Dr Ken Jones of the University of California, San Diego, for his help with the classication of congenital malformations.

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